Trial Outcomes & Findings for Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin for Multiple Myeloma (NCT NCT01177683)

Last Updated: 2023-10-06

Results Overview

In the first phase, MTD of bendamustine was determined in combination with bortezomib and pegylated liposomal doxorubicin to gain a better idea of safe dosing before proceeding with the second phase to assess efficacy. Assuming myelosuppression being a dose-limiting effect that could have been overcome with growth factor support, MTD of the combination with myeloid growth factor support was also tested.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

32 participants

Primary outcome timeframe

From C1D1 up to a maximum of 7 months or until death

Results posted on

2023-10-06

Participant Flow

Participant milestones

Participant milestones
Measure	Phase I Level 1 : Bendamustine at 90mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine: At Phase I level I, Bendamustine will be administered at 90 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase I Level 2 : Bendamustine at 120mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine: At Phase I level 2, Bendamustine will be administered at 120 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine: At phase II, Bendamustine will be administered at 90mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Doxorubicin: Pegylated liposomal doxorubicin at phase II will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase II will be administered at 1.3 mg/m2 by IV bolus or SQ injection on days 1, 4, 8, and 11 of the 28 day cycle.
Study Treatment STARTED	3	3	26
Study Treatment COMPLETED	0	0	2
Study Treatment NOT COMPLETED	3	3	24
Follow up STARTED	3	3	24
Follow up COMPLETED	0	0	0
Follow up NOT COMPLETED	3	3	24

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase I Level 1 : Bendamustine at 90mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine: At Phase I level I, Bendamustine will be administered at 90 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase I Level 2 : Bendamustine at 120mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine: At Phase I level 2, Bendamustine will be administered at 120 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine: At phase II, Bendamustine will be administered at 90mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Doxorubicin: Pegylated liposomal doxorubicin at phase II will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase II will be administered at 1.3 mg/m2 by IV bolus or SQ injection on days 1, 4, 8, and 11 of the 28 day cycle.
Study Treatment Disease Progressions during treatment	2	0	3
Study Treatment Adverse Event	0	1	12
Study Treatment Patient Withdrawal After Therapy Start	0	2	1
Study Treatment Alternative therapy	0	0	4
Study Treatment Physician Decision	1	0	1
Study Treatment Patient withdrawal before therapy start	0	0	1
Study Treatment Symptomatic Deterioration	0	0	1
Study Treatment Subject came off study without receiving any treatment.	0	0	1
Follow up Patient lost to follow up	0	0	2
Follow up Death	2	1	7
Follow up Study closed by Sponsor due slow enrollment.	1	2	15

Baseline Characteristics

Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin for Multiple Myeloma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I Level 1 : Bendamustine at 90mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. n=3 Participants Bendamustine: At Phase I level I, Bendamustine will be administered at 90 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase I Level 2 : Bendamustine at 120mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. n=3 Participants Bendamustine: At Phase I level 2, Bendamustine will be administered at 120 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. n=26 Participants Bendamustine: At phase II, Bendamustine will be administered at 90mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Doxorubicin: Pegylated liposomal doxorubicin at phase II will be administered at 30 mg/m2 by IV over 1 hour,at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase II will be administered at 1.3 mg/m2 by IV bolus or SQ injection on days 1, 4, 8, and 11 of the 28 day cycle.	Total n=32 Participants Total of all reporting groups
Age, Continuous	61.67 years n=93 Participants	53.33 years n=4 Participants	62.58 years n=27 Participants	61.63 years n=483 Participants
Sex: Female, Male Female	2 Participants n=93 Participants	2 Participants n=4 Participants	11 Participants n=27 Participants	15 Participants n=483 Participants
Sex: Female, Male Male	1 Participants n=93 Participants	1 Participants n=4 Participants	15 Participants n=27 Participants	17 Participants n=483 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants	1 Participants n=483 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=93 Participants	3 Participants n=4 Participants	25 Participants n=27 Participants	31 Participants n=483 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants	1 Participants n=483 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants	2 Participants n=4 Participants	2 Participants n=27 Participants	4 Participants n=483 Participants
Race (NIH/OMB) White	3 Participants n=93 Participants	1 Participants n=4 Participants	23 Participants n=27 Participants	27 Participants n=483 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
ECOG Performance Status (Baseline 0	1 Participants n=93 Participants	2 Participants n=4 Participants	13 Participants n=27 Participants	16 Participants n=483 Participants
ECOG Performance Status (Baseline 1	2 Participants n=93 Participants	1 Participants n=4 Participants	11 Participants n=27 Participants	14 Participants n=483 Participants
ECOG Performance Status (Baseline 2	0 Participants n=93 Participants	0 Participants n=4 Participants	2 Participants n=27 Participants	2 Participants n=483 Participants

PRIMARY outcome

Timeframe: From C1D1 up to a maximum of 7 months or until death

Outcome measures

Outcome measures
Measure	Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. n=3 Participants Bendamustine: At Phase I level 1, Bendamustine will be administered at 90 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase I Level 2:Bendamustine at 120 mg/m^2 With Bortezomib and Pegylated Liposomal n=3 Participants Bendamustine: At Phase I level 2, Bendamustine will be administered at 120 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine: At phase II, Bendamustine will be administered at 90mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Doxorubicin: Pegylated liposomal doxorubicin at phase II will be administered at 30 mg/m2 by IV over 1 hour,at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase II will be administered at 1.3 mg/m2 by IV bolus or SQ injection on days 1, 4, 8, and 11 of the 28 day cycle.
Phase I: MTD of Bendamustine When Combined With Bortezomib and Pegylated Liposomal Doxorubicin.	120 mg/m^2	120 mg/m^2	—

PRIMARY outcome

Timeframe: From C1D1 up to a maximum of 52 months or until death

Population: Two subjects never received treatment. Therefore, they were not included in any assessment of objectives.

Overall response rate (CR+PR) of bendamustine in association with bortezomib and pegylated liposomal doxorubicin was assessed in patients with relapsed or refractory Multiple Myeloma. Per modified International Myeloma Working Group criteria: Complete Response (CR) : Negative for monoclonal protein by immunofixation on the serum and urine, and Disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow ; PR : 50% or more reduction in serum M-protein and 90% or more reduction in urine M-protein or to \<200 mg/24hours or a 50% or more reduction in free light chain level ; Overall Response (OR) = CR +PR.

Outcome measures

Outcome measures
Measure	Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. n=24 Participants Bendamustine: At Phase I level 1, Bendamustine will be administered at 90 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase I Level 2:Bendamustine at 120 mg/m^2 With Bortezomib and Pegylated Liposomal Bendamustine: At Phase I level 2, Bendamustine will be administered at 120 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine: At phase II, Bendamustine will be administered at 90mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Doxorubicin: Pegylated liposomal doxorubicin at phase II will be administered at 30 mg/m2 by IV over 1 hour,at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase II will be administered at 1.3 mg/m2 by IV bolus or SQ injection on days 1, 4, 8, and 11 of the 28 day cycle.
Phase II : Overall Response Rate CR+PR	14 Participants	—	—
Phase II : Overall Response Rate Non-CR+PR	9 Participants	—	—
Phase II : Overall Response Rate Missing	1 Participants	—	—

SECONDARY outcome

Timeframe: From C1D1 until death or up to a maximum of 54 months

Population: Two subjects in phase II never received treatment. Therefore, they were not included in any assessment of objectives.

Toxicity profile (for all patients) were presented by rate of overall toxicity and rates of grade 3 or 4 toxicities analyzed separately and combined.

Outcome measures

Outcome measures
Measure	Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. n=3 Participants Bendamustine: At Phase I level 1, Bendamustine will be administered at 90 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase I Level 2:Bendamustine at 120 mg/m^2 With Bortezomib and Pegylated Liposomal n=3 Participants Bendamustine: At Phase I level 2, Bendamustine will be administered at 120 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. n=24 Participants Bendamustine: At phase II, Bendamustine will be administered at 90mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Doxorubicin: Pegylated liposomal doxorubicin at phase II will be administered at 30 mg/m2 by IV over 1 hour,at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase II will be administered at 1.3 mg/m2 by IV bolus or SQ injection on days 1, 4, 8, and 11 of the 28 day cycle.
Phase I & Phase II : Toxicity of Treatment Regimen Number of patients had at least one adverse event of any grade	3 Participants	3 Participants	24 Participants
Phase I & Phase II : Toxicity of Treatment Regimen Number of patients had at least one grade 3 or greater adverse event	2 Participants	3 Participants	19 Participants
Phase I & Phase II : Toxicity of Treatment Regimen Number of patients had at least one grade 3 or greater treatment related adverse event	2 Participants	3 Participants	14 Participants
Phase I & Phase II : Toxicity of Treatment Regimen Number of patients having serious adverse event	1 Participants	1 Participants	8 Participants

SECONDARY outcome

Timeframe: From C1D1 up to a maximum of 54 months or until death

Population: Two subjects never received treatment. Therefore, they were not included in any assessment of objectives.

The time from the start of treatment (i.e., first dose) of MM patients treated with bendamustine, bortezomib and pegylated liposomal doxorubicin to disease progression, with disease progression and death due to disease progression as events and deaths due to causes other than progression as censored. Censoring date will be the last disease evaluation date for patient without progression/death or date of death due to other diseases for patients' deaths due to other causes.Per modified International Myeloma Working Group criteria: Progressive disease (PD) is reported if any one of the following criteria is met: Increase of 25% or more in serum or urine M-protein from baseline;Serum M-protein and/or the absolute increase must be ≥0.5 g/dL;Urine M-protein and/or absolute increase must be ≥200 mg/24 hours ; Development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas;Development of hyperc.

Outcome measures

Outcome measures
Measure	Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. n=24 Participants Bendamustine: At Phase I level 1, Bendamustine will be administered at 90 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase I Level 2:Bendamustine at 120 mg/m^2 With Bortezomib and Pegylated Liposomal Bendamustine: At Phase I level 2, Bendamustine will be administered at 120 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine: At phase II, Bendamustine will be administered at 90mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Doxorubicin: Pegylated liposomal doxorubicin at phase II will be administered at 30 mg/m2 by IV over 1 hour,at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase II will be administered at 1.3 mg/m2 by IV bolus or SQ injection on days 1, 4, 8, and 11 of the 28 day cycle.
Phase II : Time to Progression	20.53 months Interval 6.47 to 27.47	—	—

SECONDARY outcome

Timeframe: From C1D1 up to a maximum of 54 months until death

Population: Two subjects never received treatment. Therefore, they were not included in any assessment of objectives.

The time from the start of treatment of MM patients treated with bendamustine, bortezomib and pegylated liposomal doxorubicin. to disease progression or death (regardless of cause of death), whichever comes first. Censoring date will be the last disease evaluation date.Per modified International Myeloma Working Group criteria: Progressive disease (PD) is reported if any one of the following criteria is met: Increase of 25% or more in serum or urine M-protein from baseline;Serum M-protein and/or the absolute increase must be ≥0.5 g/dL;Urine M-protein and/or absolute increase must be ≥200 mg/24 hours ; Development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas;Development of hyperc.

Outcome measures

Outcome measures
Measure	Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. n=24 Participants Bendamustine: At Phase I level 1, Bendamustine will be administered at 90 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase I Level 2:Bendamustine at 120 mg/m^2 With Bortezomib and Pegylated Liposomal Bendamustine: At Phase I level 2, Bendamustine will be administered at 120 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine: At phase II, Bendamustine will be administered at 90mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Doxorubicin: Pegylated liposomal doxorubicin at phase II will be administered at 30 mg/m2 by IV over 1 hour,at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase II will be administered at 1.3 mg/m2 by IV bolus or SQ injection on days 1, 4, 8, and 11 of the 28 day cycle.
Phase II: Progression-free Survival (PFS)	18.96 months Interval 6.47 to 26.91	—	—

SECONDARY outcome

Timeframe: From C1D1 up to a maximum of 52 months

Population: Two subjects never received treatment. Therefore, they were not included in any assessment of objectives.

Duration of MM patients treated with bendamustine, bortezomib and pegylated liposomal doxorubicin. from first date of at least partial response to the time of progression or death due to disease progression as events, with disease progression and death due to disease progression as events and deaths due to causes other than progression as censored. Censoring date will be the last disease evaluation date or date of death due to other causes as appropriate.

Outcome measures

Outcome measures
Measure	Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. n=24 Participants Bendamustine: At Phase I level 1, Bendamustine will be administered at 90 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase I Level 2:Bendamustine at 120 mg/m^2 With Bortezomib and Pegylated Liposomal Bendamustine: At Phase I level 2, Bendamustine will be administered at 120 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine: At phase II, Bendamustine will be administered at 90mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Doxorubicin: Pegylated liposomal doxorubicin at phase II will be administered at 30 mg/m2 by IV over 1 hour,at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase II will be administered at 1.3 mg/m2 by IV bolus or SQ injection on days 1, 4, 8, and 11 of the 28 day cycle.
Phase II: Duration of Survival	13.80 months Interval 7.85 to The upper limit could not be determined within 95% confidence interval due to low enrollment.The limited sample size is not enough to accurately estimate the upper limit of the confidence interval. A larger sample size would be needed to get a more reliable estimate.	—	—

SECONDARY outcome

Timeframe: From C1D1 up to a maximum of 54 months or until death

Population: Two subjects never received treatment. Therefore, they were not included in any assessment of objectives.

The time from the start of treatment to death from any cause with last date known alive as censoring date.

Outcome measures

Outcome measures
Measure	Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. n=24 Participants Bendamustine: At Phase I level 1, Bendamustine will be administered at 90 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase I Level 2:Bendamustine at 120 mg/m^2 With Bortezomib and Pegylated Liposomal Bendamustine: At Phase I level 2, Bendamustine will be administered at 120 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine: At phase II, Bendamustine will be administered at 90mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Doxorubicin: Pegylated liposomal doxorubicin at phase II will be administered at 30 mg/m2 by IV over 1 hour,at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase II will be administered at 1.3 mg/m2 by IV bolus or SQ injection on days 1, 4, 8, and 11 of the 28 day cycle.
Phase II: Overall Survival	30.13 months Interval 9.69 to The upper limit could not be determined within 95% confidence interval due to low enrollment.The limited sample size is not enough to accurately estimate the upper limit of the confidence interval. A larger sample size would be needed to get a more reliable estimate.	—	—

Adverse Events

Phase I Level 1 : Bendamustine at 90mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin.

Serious events: 1 serious events

Other events: 3 other events

Deaths: 2 deaths

Phase I Level 2 : Bendamustine at 120mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin.

Serious events: 1 serious events

Other events: 3 other events

Deaths: 1 deaths

Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin.

Serious events: 8 serious events

Other events: 24 other events

Deaths: 7 deaths

Serious adverse events

Other adverse events

Additional Information

Annesha Majumdar

Hoosier Cancer Research Network

Phone: 3179212050

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Phase I Level 1 : Bendamustine at 90mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. n=3 participants at risk Bendamustine: At Phase I level I, Bendamustine will be administered at 90 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase I Level 2 : Bendamustine at 120mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. n=3 participants at risk Bendamustine: At Phase I level 2, Bendamustine will be administered at 120 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000. Doxorubicin: Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle.	Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. n=26 participants at risk Bendamustine: At phase II, Bendamustine will be administered at 90mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle. Doxorubicin: Pegylated liposomal doxorubicin at phase II will be administered at 30 mg/m2 by IV over 1 hour,at day 4 of the 28 day treatment cycle. Bortezomib: Bortezomib at Phase II will be administered at 1.3 mg/m2 by IV bolus or SQ injection on days 1, 4, 8, and 11 of the 28 day cycle.
Infections and infestations INFECTION (MENINGITIS)	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	3.8% 1/26 • Number of events 1 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Infections and infestations INFECTION - OTHER (SPECIFY, __)	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	3.8% 1/26 • Number of events 1 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Infections and infestations INFECTION WITH NORMAL ANC OR GRADE 1 OR 2 NEUTROPHILS - LUNG (PNEUMONIA)	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	7.7% 2/26 • Number of events 4 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Infections and infestations INFECTION WITH NORMAL ANC OR GRADE 1 OR 2 NEUTROPHILS - UPPER AIRWAY NOS	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	3.8% 1/26 • Number of events 1 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Gastrointestinal disorders NAUSEA	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	3.8% 1/26 • Number of events 1 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Gastrointestinal disorders Dehydration	33.3% 1/3 • Number of events 1 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/26 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Infections and infestations Infection with normal ANC or Grade 1 or 2 neutrophils - Colon	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	33.3% 1/3 • Number of events 1 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/26 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Metabolism and nutrition disorders CALCIUM, SERUM-HIGH (HYPERCALCEMIA)	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	3.8% 1/26 • Number of events 1 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Gastrointestinal disorders DEHYDRATION	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	3.8% 1/26 • Number of events 2 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Gastrointestinal disorders ENTERITIS (INFLAMMATION OF THE SMALL BOWEL)	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	3.8% 1/26 • Number of events 1 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Infections and infestations FEBRILE NEUTROPENIA	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	3.8% 1/26 • Number of events 1 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Gastrointestinal disorders GASTROINTESTINAL - OTHER (SPECIFY, __)	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	3.8% 1/26 • Number of events 2 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Cardiac disorders HYPOTENSION	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	3.8% 1/26 • Number of events 1 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Metabolism and nutrition disorders SODIUM, SERUM-LOW (HYPONATREMIA)	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	3.8% 1/26 • Number of events 1 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Cardiac disorders SUPRAVENTRICULAR AND NODAL ARRHYTHMIA - ATRIAL FIBRILLATION	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	3.8% 1/26 • Number of events 1 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.
Gastrointestinal disorders VOMITING	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	0.00% 0/3 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.	3.8% 1/26 • Number of events 1 • From C1D1 up to at least 30 days after final protocol treatment or up to a maximum of 54 months. Adverse events will be recorded from the time of consent and for at least 30 days after final protocol treatment. SAEs must be reported during the course of the study within 24 hours of discovery of the event.